This UOl application brings together three Principal Investigators (Drs. Orkin, Armstrong, and Roberts) to exploit genetically engineered mouse models of devastating human pediatric cancers for the development of new therapeutic avenues. A common theme in these projects is understanding the role of epigenetics in cancer initiation and/or progression. In Project 1, "New approaches to osteosarcoma", the involvement of the polycomb repressive complex PRC2, which is overactive in many malignancies as well as in the mouse model of osteosarcoma, will be addressed by a multidisciplinary and integrated biochemical and genetic strategies. In parallel, efforts will be directed toward high-throughput screens to identify agents that induce differentiation of osteosarcoma cells or selectively kill cells deficient in both p53 and Rb (as in the case of this cancer). Project 2, "Epigenetic programs in leukemia development and drug response", will focus on the roles of DNA methylation and PRC2 in leukemias due to translocations involving the MLL locus. In addition, efforts will concentrate on high-throughput screening to identify inhibitors of D0T1L, the H3K79 histone methyltransferase associated with MLL-fusion proteins. Project 3, "Epigenetics in cancer initiation and progression: from mechanism to therapy", focuses on malignancies due to SNF5 inactivation, as these appear to be "epigenetically driven" and without evident somatic mutations. The interactions between SNF5 and MLL or PRC2 will be tested genetically, and thereafter drugs that target epigenetic pathways will be tested for efficacy in SNF5-deficinet cancer in the mouse. This U01 program is highly integrated as the mouse models affecting epigenetic pathways are shared among the projects. In addition to providing a highly interactive framework, this integration will allow for identification of features that are either common or specific for these malignancies.